USE OF LITHIUM SALTS FOR REDUCING STRUCTURAL DEFECTS IN A HUMAN LENS

Abstract: The invention provides a composition and method for reducing structural defects in the lens of an eye. Structural defects represent spaces or vacancies in the structural order of the crystalline lens, which can be restored to the predefect order through the use of structure makers. These structure makers occupy the space or vacancy of the defect, restoring the order of the system. Lithium ions are used as a preferred structure maker to reduce the structural defects that lead to cataract in a human lens.

Description: OF LITHIUM SALTS FOR REDUCING STRUCTURAL DEFECTS IN A HUMAN LENS Field of the Invention This invention relates in general to a composition and method for reducing structural changes (defects) and preventing their subsequent effects in the lens of the eye, and more particularly to the use of structure makers such as lithium ions, and other small ions having high charge density, to reduce and/or prevent cataract formation in the human crystalline lens. Background of the Invention Age is a significant risk factor in cataract formation. Such cataracts that develop in the elderly are referred to as senile cataracts. Cataracts can also be caused by trauma or as by¬ products of disease, or be congenital in nature. Cataracts are also thought to result from the use of certain drugs, such as alcohol [see J.J. Harding and R. Van Heyningen, British Journal of Ophthalmology 22 . .809-814 (1988)], phenothiazine drugs and haloperidol [see N.E. Isaac et al., Arch Ophthalmol 109:256-260 (1991)], and allopurinol [see W.K. Clair et al., British Journal of Ophthalmology 73:173-176 (1989) ] . In any type of cataract, the opacification (devitrification) of the crystalline lens is the chief cause of the visual loss in individuals with this condition. It is therefore desirable to find a method of reducing and/or preventing cataracts. Certain drugs are thought to have a protective or beneficial effect on the development of cataracts, such as aspirin, aspirin-like analgesics (paracetamol, ibuprofen) , and cyclopenthiazide (a diuretic) . See J.J. Harding et al., Acta Ophthalmologica «T7:518-524 (1989); J.J. Harding and R. Van Heyningen, British Journal of Ophthalmology 71:809-814 (1988); J.M. Seddon et al. , Arch Ophthalmol 109:252-255 (1991); B.E.K. Klein et al. , Diabetes Care 1/2:495-499 (1987) ; and H. Cheng, British Journal of Ophthalmology 2ϋ:257 (1992). Although several drugs are currently used or under investigation for such reduction or protection, a need continues to exist for an efficacious method of reducing and/or preventing cataract formation which can readily be used without adverse side effects on humans. Summary of the Invention This need is met by the composition and method according to the subject invention. A composition is provided for reduction of structural changes (defects) of the metastable systems comprising the lens of the eye. The composition comprises defect- reducing amounts of a structure maker and a physiologically acceptable carrier. Also provided is a method for reducing defects in a lens which comprises selecting a defect-ridden lens, and exposing the lens to a structural defect- reducing amount of a structure maker. The lens may be exposed ex situ to the structure maker, and once the structure maker has reduced the structural defects of the metastable tissue system, the lens may then be returned to its jln situ site. In all cases, the structure maker reduces or eliminates the structural defects and therefore prevents the subsequent formation of further pathology in the metastable systems comprising the lens so treated. Structural defects can occur in the molecules in lenses, and these defects can be detected by measuring the photoluminescence of the lenses. [See J. Schroeder, et al., Mat. Res. Symp. Proc. 272: 251- 263 (1992)]. Photoluminescence is an indicator that microscopic and/or macroscopic defects exist in the ordering of the system, irrespective of whether the system is a solid state system or a biological system. In either type of system, the photoluminescent spectral response of the system provides evidence for the presence or absence (or the repair) of microscopic structural defects within that system. For example, in the metastable system that comprises the crystalline lens of the eye, an increase in the photoluminescence intensity occurs over time with the magnitude of photoluminescence increasing with age. [See also the confirmation of this effect called autofluorescence (sic) in the work of P.J. Airaksinen et al., Invest. Ophthal. Vis. Sci. 34: 762 (1993 Suppl.)]. Structural defects in the tissue of the lens of the eye are believed to be the precursor modes for formation of cataracts. These structural defects manifest themselves in changes to the photoluminescence response spectrum of the lens. If plotted as intensity versus wavelength, the photoluminescence spectra exhibit a change in intensity, a broadening of the spectral band width, and a shift in the wavelengths of the peak toward longer wavelengths with age. Thus, the presence of structural defects that eventuate in a clinical cataract can be detected by measuring the photoluminescence response of the lens and determining its deviation from the norm. In vitro and in vivo measurements of photoluminescence of a lens can be made using a Raman Spectrometer system comprising an Argon-ion Laser (manufactured by Spectra Physics, Mountain View, California) and a Spex Double Monochromator (manufactured by Spex Industries, Metuchen, New Jersey) with subsequent photon counting, detection and stabilization equipment, and a data handling microprocessor also provided by Spex Industries. Structure makers as used herein refer to ions of very high charge density and very low mass and small ionic radii that can restore order and in turn can affect the degree of devitrification of the metastable system. A structural defect can be viewed as a space or vacancy of microscopic dimensions (molecular or atomic in size) within the structure of the system. The structure maker occupies that space or vacancy to return the structure to a state having the same order as existed before the defect was produced. The degree of order of the system, which relies on the presence or absence of such structural defects, can be severely influenced by the number of these defects. Structure makers are known in the field of aqueous electrolyte solutions to accomplish a similar ordering of the system, and generally include ions smaller and more highly charged than potassium (K + ) . Such structure makers include, for example, lithium (Li + ) , fluorine (F) , calcium (Ca 2+ ) , and the hydroxyl radical (OH " ) . The compositions of the subject invention utilize the structure makers to reduce and/or repair structural defects. If a structure maker is present in the intermolecular spaces of the lens tissue when a perturbation results in a structural defect, then the presence of the structure maker causes an immediate restoration of the predefect order in the system. Lithium salts such as lithium chloride and lithium carbonate are preferred because at suitable doses they are well tolerated by humans who can ingest in excess of one gram/day for extended periods of time without significant untoward risk. Brief Description of the Figures These features and advantages of this invention will be evident from the following detailed description of preferred embodiments when read in conjunction with the accompanying drawings in which: Fig. 1 is a graph showing the red-shift of photoluminescence spectral peak position versus age for eight (8) in vitro human lenses; Fig. 2 is a graph showing photoluminescence peak intensity versus age for the same set of human lenses as shown in Fig. 1; and Fig. 3 is a graph showing photoluminescence intensity versus wavelength for four * (4) in vitro human lenses. Detailed Description of the Invention This invention teaches that no description of the transmission of electromagnetic waves (light) through biological tissues will be complete without measuring and understanding photoluminescence and absorption, as well as the scattering of the light, in the tissue medium. These three factors, photoluminescence, absorption and scattering, together determine the fate of any electromagnetic wave (ray of light) that passes through any tissue. All three factors change with external perturbations and time (age) in determinable and deterministic ways. In cataract, photoluminescence, absorption and scattering of electromagnetic waves are elevated relative to age-matched lenses. The elevation can be detected in the retinal plane of the eye by visual tests suitably designed to reflect such elevations. The measured magnitudes of these three factors in all cases are determined by the nano-structural (mesoscopic) details of the tissue, namely, the defects or nano-inhomogeneities that exist in the molecular make-up of the tissue. In lenses, which exhibit properties found in metastable systems, and which exhibit defects (as determined by their response to optical excitation) , the incidence of defect migration and subsequent folding and multiplication can be inhibited by the incorporation of certain classes of ions into the lens tissues. These classes of ions are generally grouped under the generic term of "structure makers". In general, the structure makers will * consist of ions of small ionic radii and well-defined high charge densities, for example lithium ions. The mechanisms of the structural changes and the eventual devitrification process leading to senile cataract formation are similar to those that exist in a solid solution. Over time the process is initially on a microscopic scale (i.e., dimensions of several nanometers) . However, with further degradation, macroscopic dimensions are achieved (i.e., micron size) with the consequent onset of a pathological state (as exhibited by the changes in the transparency that occur in the cataractous lens which manifests itself in increased scatter, photoluminescence and absorption) . Measurements have shown, for example, that in vitro lenses immersed in a physiological saline (NaCl) solution, 20% of which is LiCl, a structure maker, brings about beneficial changes in these human lenses as exhibited by precise optical measurements. These changes can be interpreted as a reversal of the normal aging process of the lens. The data for treatment with a non-structure maker (KC1) when comprising 20% of a physiological saline solution show no comparable beneficial effect. These results are given in Table 1. Eyes from the same donor were employed in the comparison of the structure maker to non-structure maker, i.e., one eye of the donor was exposed to the structure maker, LiCl, while the opposite eye was exposed to the non-structure maker, KC1. Referring to Fig. 1, the substantially linear increase of the position of the photoluminescent peak of lenses by age is shown. The linear progression establishes that as the lens ages, a shift to longer wavelengths (i.e. red-shift) in peak position occurs which is indicative of an increase in structural defects within the lens system. Referring to Fig. 2, the intensity of the peak photoluminescence is plotted as a function of age, again showing an increase over time. If log of intensity were plotted, a linear progression would be seen, establishing that as the lens gets older, an increase in peak intensity occurs which is also indicative of an increase in structural defects within the lens system. Fig. 3 shows the photoluminescence intensity plotted against wavelength for four human donor lenses of various ages (74 years, 50 years, 25 years, and 7 years) . The exciting wavelength is 488 nm. Note that as defects increase in the lenses due to the increasing age of the donor, there is an increase in the peak intensity, a broadening of the spectral band (i.e., the full width of the peak at half maximum photoluminescence intensity) , and a shift in the wavelength of the peak. These three changes are characteristic of the presence of increasing structural defects within these systems. This analysis is supported by similar spectral behavior in a glass, a disordered solid system, where the three spectral properties of photoluminescence, absorption and scattering change similarly as structural defects increase and the solid becomes more devitrified. [See J. Schroeder, Light Scattering of Glass. Treatise on Materials Science and Technology, Vol. 12, Glass 1: Interaction with Electromagnetic Radiation (1977), pp. 157-222, Academic Press Inc., New York; and J. Schroeder et al., Mat. Res. Soc. Symp. Proc. 272: 251-263 (1992)]. The effect of the structure makers on these characteristic age changes of the human lens was determined by immersing one each of a matched pair of lenses for at least one hour at room temperature in a physiological saline solution (NaCl) , 20% of which consisted of iso olar lithium chloride (LiCl) or isomolar potassium chloride (KC1) . The results of these tests are shown in Table 1. With lithium ion treatment, the shift of the peak position to a longer wavelength is reversed, i.e. the mean peak wavelength before treatment was 532.4 ran, and the mean position after treatment with a structure maker was 527.9 nm. This decrease in the mean peak position (-4.5 nm shift) is indicative of a reduction in the number of structural defects as discussed above and is equivalent in both donors to the number of structural defects that would accumulate in a fourteen year period. When a non-structure maker bath is used, the mean shift is only -0.6 nm. Thus it is clear that structure makers such as lithium salts are able to alter the structural defects of the lens and produce a blue-shift in the peak of the photoluminescence spectrum. These observations of in vitro human donor lenses treated with lithium ions are consistent with the protection afforded against selenium induced cataracts in Wistar suckling rats. [X.R. Huang, et al.. Invest. Ophthal. Vis. Sci. 34_: 1064 (1993 Suppl.) ] . As discussed above, the in vitro donor lenses were exposed to lithium ions by immersion in a solution containing lithium salts. The lithium ions could also be administered in vivo in the form of eye drops which would permit a smaller total dose to be more localized to the crystalline lens. Moreover, diffusion of the lithium ions to the lens or other tissue is facilitated by iontophoresis, the small diameter of the lithium ions lending itself admirably to this route of entry. If confined to this, route of entry, 30 mg of LiCl/day in an isomolar physiological saline carrier provides an efficacious dose. However, where a systemic route must be employed, larger daily doses will require dosages on the order of 750 g/day. Still higher concentrations may be employed with immersion techniques, however the excess structure makers would be removed before the tissue was replaced. In summary, the data show that ions identified as structure makers, such as lithium, are an effective treatment for lenticular structural defect management and an effective means to alter opacifying structural defects in lenses in which there is an increased photoluminescence, absorption and scatter resulting from disorder in the nanostructural matrix. Table 1 Blueshift in the Peak Photoluminescence Values With Treatment 20% Li + 20% K + before v = 526.7nm v u = 526.2nm treatment* v i 2 - 538.Onm v 12 = 537.Onm after v = 522.4nm v = 525.2nm treatment* v 12 = 533.3nm v l 2 = 536.8nm variation due Δj = -4.3nm Δi = -l.Onm to treatment Δ 2 = -4.7nm A = -0.2nm * treatment consists of immersion for at least one hour at room temperature in isotonic saline solution (NaCl) 20% of which consists of isomolar lithium chloride, or potassium chloride Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined by the following claims.

Claims: What is claimed is: 1. A composition for reduction of structural defects in a lens, said composition comprising: a structural defect-reducing amount of a lithium salt; and a physiologically acceptable aqueous carrier adapted for instillation into an eye. 2. The composition of claim 1 wherein said lithium salt comprises lithium chloride. 3. The composition of claim 1 wherein said lithium salt comprises lithium carbonate. 4. The composition of claim 1 wherein said physiologically acceptable carrier comprises an isotonic saline solution. 5. The composition of claim 1 adapted for iontophoretic application. 6. A composition for reducing opacification in a cataract of a human lens, said composition comprising: an opacification-reducing amount of a lithium salt; and a physiologically acceptable carrier adapted for instillation into an eye. 7. A method of reducing structural defects in a lens which comprises: selecting a lens having structural defects therein; and exposing said lens to a structure maker, said structure maker reducing said structural defects in said lens. 8. The method of claim 7 wherein said structural defects comprise cataract precursors in said lens. 9. The method of claim 7 wherein said structure maker comprises a source of lithium ions. 10. The method of claim 9 wherein said source of lithium ions comprises lithium chloride. 11. The method of claim 9 wherein said source of lithium ions comprises lithium carbonate. 12. A method of reducing opacification in a cataract of a human lens, said method comprising: selecting a human lens having opacification due to a cataract therein; and exposing said human lens to a source of lithium ions, said lithium ions reducing said opacification in said cataract of said human lens. 13. The use of a structure maker for the manufacture of a medicament for reducing structural defects in a lens by exposing said lens to said structure maker. 14. The use according to claim 13 wherein said structural defect comprises a cataract in said lens. 15. The use according to claim 13 wherein said structure maker comprises a source of lithium ions. 16. The use according to claim 15 wherein said source of lithium ions comprises lithium chloride. 17. The use according to claim 15 wherein said source of lithium ions comprises lithium carbonate. *****

Inventors: KANDEL GILLRAY L, SCHROEDER JOHN, KANDEL, GILLRAY, L., SCHROEDER, JOHN
Applicants: RENSSELAER POLYTECH INST, RENSSELAER POLYTECHNIC INSTITUTE
Application year: 1994
Main classification: A61K33
IPC codes: A61K33